Cataracts are the leading cause of blindness. Millions of patients every year undergo cataract surgery to remove the opacified lenses. Surgical treatment of cataracts, while effective, is not without risk of complications. It has been reported that congenital cataract is one of the common causes of visual impairment and childhood blindness. Congenital cataract occurs in an isolated fashion or as one component of a multi-system disorder. Nonsyndromic congenital cataracts have an estimated incidence of 1-6 per 10,000 live births. Nearly one-third of the cases show a positive family history, of which autosomal dominant inheritance is the most common. More than 20 genes have been identified responsible for isolated autosomal dominant congenital cataract. These genes encode crystallins, membrane transport proteins, cytoskeletal protein, and transcription factors. Crystallin proteins, including α-, β- and γ-crystallins, represent about 90% of lens soluble proteins in human. These proteins play critical roles in the optical transparency and high refractive index. α-Crystallins belong to the family of the small heat-shock proteins, acting as a molecular chaperone that protects proteins from misfolding. β- and γ-Crystallins, considered as a superfamily, are lens structural proteins and share a common two-domain structure, composed of four Greek-key motifs. γ-Crystallins include six members encoded by a gene cluster (CRYGA-F) on human chromosome 2. See Xiao-Qiao Li et al., Human Mutation, Research Article, Vol. 33, Issue 2, pp. 391-401, February 2012.
Zhao et al. (2015) The human lens is comprised largely of crystallin proteins assembled into a highly ordered, interactive macro-structure essential for lens transparency and refractive index. Any disruption of intra- or inter-protein interactions will alter this delicate structure, exposing hydrophobic surfaces, with consequent protein aggregation and cataract formation. Cataracts are the most common cause of blindness worldwide, affecting tens of millions of people, and currently the only treatment is surgical removal of cataractous lenses. The precise mechanisms by which lens proteins both prevent aggregation and maintain lens transparency are largely unknown. Lanosterol is an amphipathic molecule enriched in the lens. It is synthesized by lanosterol synthase (LSS) in a key cyclization reaction of a cholesterol synthesis pathway. Two distinct homozygous LSS missense mutations (W581R and G588S) in two families with extensive congenital cataracts. Both of these mutations affect highly conserved amino acid residues and impair key catalytic functions of LSS. Engineered expression of wild-type, but not mutant, LSS prevents intracellular protein aggregation of various cataract-causing mutant crystallins. Treatment by lanosterol, but not cholesterol, significantly decreased preformed protein aggregates both in vitro and in cell-transfection experiments. Zhao et al. have also demonstrated that lanosterol treatment could reduce cataract severity and increase transparency in dissected rabbit cataractous lenses in vitro and cataract severity in vivo in dogs. Zhao et al. identified lanosterol as an important compound in the prevention of lens protein aggregation and suggested a novel strategy for cataract prevention and treatment. See Ling Zhao et al., Lanosterol reverses protein aggregation in cataract, Nature, Research Letters, July, 2015. Similarly, Makley et al., Science, Vol. 350, Issue 6261, pp. 674-677, reported the administration of certain sterols as pharmacological chaperones for α-crystallin for partially restoring transparency in cataract models.
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